Drug eruption is a representative skin disorder caused by a drug (cutaneous adverse drug reaction; cADR) characterized by acute inflammatory reaction on skin and mucosa induced by a drug. Drug eruptions are dose-independent and unpredictable, and often life-threatening. Drug eruptions include those having a wide range of symptoms, from mild to severe, and examples of drug eruptions having severe symptoms include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS), which are known as three major severe drug eruptions.
Almost all drugs reportedly have a risk to cause drug eruption, and above all, the antiepileptic drug carbamazepine (CBZ) is known to cause a variety of drug eruptions including SJS, TEN, and DIHS.
From previous studies, onset of drug eruption has been considered to involve T cell-mediated allergic reaction but its detailed mechanism of pathogenesis is unclear. Moreover, reactivation of human herpes virus 6 (HHV-6) is suggested to contribute to symptoms of DIHS such as fever and hepatitis but its mechanism of pathogenesis is obscure.
A study of CBZ using Taiwanese subjects has indicated that human leukocyte antigen (HLA)-B*1502 allele is strongly associated with SJS and TEN induced by CBZ (Non-Patent Document 1). However, allele frequencies of HLA loci are significantly different among different ethnic groups and HLA-B*1502 allele, for example, is found at a frequency of 8.6% in the Southeast Asian populations (Non-Patent Document 1), but only at a frequency of 0.1% in the Japanese and Caucasian populations (www.allelefrequencies.net). Therefore, HLA-B*1502 allele is not seen as a genetic factor useful for prediction of SJS and TEN induced by CBZ in the Japanese and Caucasian populations.
Recently, the relationship between HLA-A*31:01 allele and cADR induced by CBZ (CBZ-induced cADR) in Japanese subjects was revealed. That is, HLA-A*31:01 allele was present in 60.7% of the patients with CBZ-induced cADR, but only in 12.5% of the CBZ-tolerant subjects (odds ratio=10.8, P=3.64×10−15) (Non-Patent Document 2). Moreover, the relationship between HLA-A*31:01 allele and CBZ-induced cADR is reported also in the European populations (Non-Patent Document 3). Therefore, a pharmacogenetic test to identify subjects carrying HLA-A*31:01 allele will be useful to reduce the incidence of CBZ-induced cADR in both the Japanese and European populations.
Several HLA genotyping methods have been reported (Non-Patent Documents 4 to 6). Because the methods were labor-intensive and time-consuming, they had room for improvements. Moreover, a next-generation DNA sequencer is used recently to perform HLA genotyping (Non-Patent Documents 7 to 9), but it requires long reaction time and high cost and therefore the genotyping remains to be improved.
Moreover, detection of HLA-A*31:01 allele by combining a PCR assay and Invader assay is unknown.